1H-tetrazole-5-carboxamides

ABSTRACT

Anti-allergic agents of N-aromatic and N-heterocyclic 1H-(or 2H) tetrazole-5-carboxamide derivation present the following formulae: ##STR1## in which A is a member selected from the group consisting of 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2, 3, 4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxy oxalyloxy)ethoxy, N-mono- and di-lower alkylamino(lower)-alkoxy, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl, mono- and di- lower alkylamino, carboxy, lower alkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals; 
     And pharmaceutically acceptable salts thereof.

RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 542,465, filed Jan. 20, 1975 now U.S. Pat. No. 3,966,965; which in turn is a continuation-in-part of Ser. No. 344,466, filed Mar. 23, 1973, now abandoned.

BACKGROUND OF THE INVENTION

Atopic immediate sensitivity is the chief manifestation found in animals suffering from bronchial asthma, seasonal pollinosis (e.g. hay fever), allergic rhinitis, urticaria, allergic conjunctivities, food allergies and anaphylactoid reactions. The substances most frequently responsible for clinically manifest sensitivities are plant pollen, animal feathers and danders, dust, milk and wheat, whether inhaled or injested. Atopic hypersensitivity is found in man, dog and other animals. Its occurrance is exceptionally found in the lower animals.

The presence of antibodies associated with atopic hypersensitivity reactions in the host serum is established by the passive sensitization of the skin of a normal recipient, after injection of serum from a sensitized host into a skin site followed by injection of antigen into the same area 24 hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity possesses distinctive features in that it does not in all forms precipitate with its antigen, fails to pass the placenta from mother to fetus, has special affinity for the skin, frequently lacks specificity toward an individual antigenic factor and is usually labile at about 56° C. after 2 hours.

The homocytotropic antibody found in or induced in the rat is related in function and reaction to immunoglobulin E (reagin or IgE) found in the human. The correlation between homocytotropic antibody in the rat and IgE in the human has been established through the common effects obtained from chemical reactions, immunological reactions and drug responses in the two species hosting those antibodies. In the human, reagin is the antibody responsible for atopic immediate hypersensitive reactions. In the rat, the homocytotropic antibody is responsible for atopic immediate hypersensitive reactions.

In theory, reagin, influences the cell membrane of a mast cell by reacting with an antigen, to initiate the reaction(s) within the mast cell which ultimately releases a mediator such as Bradykinin, SRS-A (slow reacting substance-A), histamine and other unknown substances. The mediator effects a change in surrounding cell wall permeability permitting a rapid change in flow or exudance of mediator(s) from the cells, resulting in an allergic attack symptom. The various methods commonly employed to relieve the symptoms of allergic attack, none of which are considered to be quite acceptable, are to (1) avoid attack by the antigen, (2) block the production of antibody with an immunosuppressant, (3) block the action of the mediators on the cell under attack by administration of anti-histaminics, anti-5-hydroxy-tryptamines(5-HT) or anti-inflammatories, or (4) stimulate the cell under attack to negate the action of the mediator through the action of bronchodilators such as Isuprel® or a Xanthine.

A compound typifying anti-allergic activity by blocking reaction(s) within the mast cells, thereby preventing the production and release of mediators, is disodium cromoglycate. (INTAL®).

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a process for preventing the release of pharmacological mediators from an immediate hypersensitivity reaction reaginic type antibodies and an antigen, thereby preventing the symptoms manifest in bronchial asthma, seasonal pollinosis, allergic rhinitis, urticaria, allergic conjunctivities, food allergy and anaphylactoid reactions of a sensitized animal, which comprises prophylactically administering to said animal an effective amount of a compound of the formula: ##STR2## in which A is a member selected from the group consisting of 2-thiazolyl, 2-pyridyl, 3-(lower) alkyl-2-pyridyl, 6-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxy oxalyloxy) ethoxy, N-mono- and di-lower alkylaminoalkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl, mono- and di-lower alkylamino, carboxy, lower alkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower) alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals;

and pharmaceutically acceptable salts thereof.

The preferred method aspect of this invention comprises administering to a sensitized animal a compound of the formula: ##STR3## in which R¹, R² and R³ are hydrogen;

or

R¹ is --CN or --CONH₂ ;

R² is lower alkoxy, hydroxy lower alkoxy, lower alkylamino or di(lower)alkylamino;

R³ is hydrogen, lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb(lower)alkoxy;

or a pharmaceutically acceptable salt thereof.

The novel N-aromatic and N-heterocyclic 1H-tetrazole-5-carboxamides form an additional aspect of this invention. They present the structural formula: ##STR4## in which A is 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, 2,6-dichlorophenyl and substituted phenyl moieties having from one to three substituents selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxy oxalyloxy)ethoxy, N-mono- and di(lower)alkylamino(lower)alkoxy, sulfamyl, polyhalo(lower)alkyl, carbamoyl, N-(lower)alkylcarbamyl, mono- and di-(lower)alkylamino, carboxy, lower alkyl carbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy;

and pharmaceutically acceptable salts thereof.

The preferred compounds are those of the structural formula: ##STR5## in which R¹, R² and R³ are hydrogen;

or

R¹ is --CN or --CONH₂ ;

R² is lower alkoxy, hydroxy lower alkoxy, lower alkylamino or di(lower)alkylamino;

R³ is hydrogen, lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb(lower) alkoxy;

or a pharmaceutically acceptable salt thereof.

The term "lower" used throughout this application to modify alkyl, alkoxy, and the like, is intended to embrace univalent aliphatic hydrocarbon radicals containing from 1 to 6 carbon atoms. The term "halo" is used to embrace chlorine, bromine, iodine and fluorine. The expression "pharmaceutically acceptable salt " is intended to embrace acid addition salts, where applicable or 1H-tetrazole alkali metal or amine salts. Examples of acid addition salts include both organic and inorganic non-toxic salt formed with acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like. The alkali metal or amine salts of the 1H-tetrazole include sodium, potassium, lower alkylamine (e.g. methylamine, ethylamine, propylamine, etc.) di(lower)alkylamine (e.g. dimethylamine, diethylamine, dipropylamine, etc), di(hydroxyethyl)amine, N,N¹ -dibenzyl ethylene diamine, and the like.

The N-substituted tetrazole-5-carboxamide products of this invention may appear in either the 1H or 2H tautomeric forms. It is applicants'intention, throughout this specification and in the appended claims, to embrace the 2H tautomer as well as the 1H tautomer, both by the structural depictation of the 1H tautomer and by naming the 1H derivatives. The relationship between the tautomers is as follows: ##STR6##

The compounds disclosed in this application relieve atopic allergic manifestations, when administered orally and parenterally to sensitized rats.

The technique employed to establish the anti-allergic activity of the 1H-tetrazole-5-carboxamide derivatives is reported in Immunology, vol. 16, pp. 749-760 (1969) and involves four male Charles River rats (200-250 grams body weight) per group to provide a control, a host for administration of a standard anti-allergic compound (disodium cromoglycate) and animals for the test compound. The rats were injected intracutaneously on their shaved backs with sera from rats immunized with egg albumin and pertussis vaccine. Twenty-four hours after the initial injections, the test compound is administered intraperitoneally or orally at a dosage level of 200 milligrams per kilogram host body weight or less. Five minutes later 1 milliliter of a 0.5 percent solution of Evans blue dye and 8 milligrams of egg albumin is injected intravenously. After 40 minutes, the animal is sacrificed and the bleb size on its back is measured. The mean bleb size for the animals administered the test compound is calculated and the percent inhibition is determined by comparison with the control animal.

Although the mechanism by which the compounds of this invention function is not absolutely known, applicants have found that the compounds of this invention, in a manner believed to be similar to the function of INTAL²⁰⁰, block reaction(s) in the mast cell leading to the production and release of mediators.

The compounds of this invention permit the occurrence of a non-productive antigen-antibody interaction. They effectively block the IgE type reaction and have little or no effect on the other immunoglobulins such as IgG, IgM, IgA and IgD.

In other words, the compounds of this invention block the release of mediators commonly resulting from the anitgen-antibody reaction as exemplified in a passive cutaneous anaphylaxis test (PCA) using rat homocytotropic antibody -- a known correlate of human reaginic antibody.

By analogy to disodium cromoglycate and its activity correlation between standard test animals, domestic animals and man, the compounds of this invention have been established an anti-allergic agents suitable for the same uses at analogous doses and through the same route of administration as INTAL®.

Thus, there is provided herewith a method for suppressing allergic manifestations of atopic immediate sensitivity in warm-blooded, human and non-human animals, the latter including domesticated animals such as the mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow, and the like, by administering an effective amount of one or more of the compounds disclosed in this application by oral, topical, parenteral, rectal, vaginal or inhalation routes. The compounds of this invention may be administered in conjunction with known compounds effecting anti-histaminic, anti-hypertensive, analgesic, central nervous system depressant, immunosuppressive, anti-serotonin, anti-Bradykinin or endocrinological responses. In addition, those conventional adjuvants known to the art may be combined with the anti-allergics of this invention to provide compositions and solutions for administrative purposes, although it is considered desirable and feasible to employ the anti-allergics as neat or pure compounds without additives other than for purposes of providing suitable pharmaceutical solution or liquid or vapor suspensions, the latter for use as inhalants.

The oral dose range lies from below 0.1 milligram per kilogram to about 50 milligrams per kilogram host body weight. As an inhalant the dose is from that of INTAL®, (about 20 milligrams) to 1/20th that quantity administered as needed prior to attack. Thus the dosage contemplated for human use based upon the potency of the compounds administered lies from about 5 milligrams to 1 gram, preferably 50 milligrams to about 750 milligrams in unit dosage form to be administered when necessary and to the degree of the desired response, in single or plural doses under the guidance of physician.

An especially advantageous process for the production of the N-aromatic and N-heterocyclic 1H- (or 2H) tetrazole-5-carboxamide derivatives of this invention, because of its broad applicability, involves reaction of the amine ANH₂ with 1-protected 1H-tetrazole-5-carbonyl chloride followed by deprotection (hydro-genolysis) and conversion to a pharmaceutically acceptable non-toxic salt as desired. This process was invented by Dieter H. Klaubert and John H. Sellstedt and is the subject matter of copending application Ser. No. 669,570, filed on even date herewith. Protection of the tetrazole may be accomplished with any group conventionally employed for that purpose such as benzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, trichloroethyl, and the like. Where the group A of the amine reactant ANH₂, contains a group which will react with an acid chloride, that group is also protected during the acylation. Illustrative of such groups is the monoalkylamino group, which may be effectively protected by the trimethyl silyl group, which protecting group is readily removed subsequently.

More specifically, the process involved in producing the anti-allergic agents disclosed herein may be described as a process for the production of a 1H-(2H)-tetrazole-5-carboxamide which comprises

a. reacting an N-protected oxamic acid lower alkyl ester with PCl₅ in the presence of an acid acceptor to obtain the imidochloride ##STR7## b. cyclizing said imido-chloride with hydrazoic acid to produce the ester 1-R⁷ -5-carboethoxy-1H-tetrazole;

c. Saponifying said ester to obtain an alkali metal salt of said tetrazole;

d. converting said tetrazole salt to the 5-chlorocarbonyl-1- R⁷ -1H-tetrazole by reaction with a chlorinating agent;

e. reacting the 5-chlorocarbonyl-1-R⁷ -1H-tetrazole with an amine of the formula ANH₂ ;

f. removing the 1-R⁷ group from the product of step (e) to obtain the N-substituted-1H-(or 2H) tetrazole-5-carboxamide of the formula ##STR8## wherein A is a member selected from the group consisting of 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxy oxalyloxy) ethoxy, N-mono- and di- lower alkylamino(lower)alkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamoyl, N-lower alkylcarbamoyl, mono- and di-lower alkylamino, carboxy, lower alkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy radicals;

R⁶ is lower alkyl;

and

R⁷ is the N-protecting group.

The pharmaceutically acceptable salts of the products of the above described process are prepared by conventional means. The reactants ANH₂ are known compounds or may be readily prepared by techniques well known in the art. Examples of the preparation of various ANH₂ reactants are presented in the parent, copending application Ser. No. 542,465, filed Jan. 20, 1975, which application is incorporated herein by reference for that purpose.

In the formation of the 1H-tetrazole-5-carboxylic acid ester from the imido-chloride precursor, the reactant hydrazoic acid may be produced in situ from, for example, a metal azide, trimethylsilylazide or ammonium azide. It is intended, throughout this specification that the expression hydrazoic acid should be interpreted as encompassing the metal azides, trimethylsilylazide and ammonium azide.

The chlorinating agent employed in step (d) of the process described, supra, is any such agent conventionally employed in the production of carboxylic acid chlorides such as phosphorus pentachloride, phosphorus trichloride, thionyl chloride, and the like.

EXAMPLE 1 1H-Tetrazole-5-carboxanilide

The title compound was prepared by the method of B. E. Fisher, et al., J. Org. Chem., 24, 1650(1959). It is crystallized from ethanol-water, m.p. 216°-218° C. (dec.). The title compound exhibits 100 percent inhibition of the mean bleb size of sensitized rats when tested orally and intraperitoneally at 200 milligrams per kilogram host body weight in accordance with the rat PCA test described, supra.

EXAMPLE 2 N-[2-Carbamoyl-3-methoxyphenyl]-1H-tetrazole-5-carboxamide

To a solution of 20.72 g. (0.1 mol.) of benzyloxamic acid ethyl ester and 9.89 g. (0.125 mol.) of pyridine in 95 ml. of methylene chloride is added 26.03 g. (0.125 mol) of PCl₅ slowly through a Gooch tube at 30° C. or less. Stir 1 hour at room temperature, add 112 ml. of 1.78 molar hydrazoic acid in benzene, stir 1 hour at room temperature, and slowly bring to reflux. After 41/2 hour of reflux, keep the reaction mixture over night at room temperature. The reaction mixture is poured into a cold NaHCO₃ solution, diethyl ether is added and separate the layers. The organic layer is washed again with a NaHCO₃ solution, with N HCl, with brine and dried with CaCl₂. Evaporation of the solvent gives 22.46 g. of oil which is distilled in a falling film molecular still at 135° C. and 0.15 mm, giving 11.12 g. of product. The oil is crystallized from diethyl ether-pentane to give 6.88 g. of 1-benzyl-1H-tetrazole-5-carboxylic acid ethyl ester, m.p. 51°-55° C.

Anal. for: C₁₁ H₁₂ N₄ O₂ : Calculated: C, 56.89; H, 5.21; N, 24.13; Found: C, 56.58; H, 5.11; N, 24.13.

The ethyl ester (11.61 g., 0.05 mol.) is dissolved in 60 ml. of warm absolute ethyl alcohol. Addition of 3.96 g. (0.06 mol.) of KOH in 7 ml. of water causes crystallization of the potassium salt. The mixture is kept at room temperature over night, filtered and the filter cake is washed with cold absolute ethyl alcohol and diethyl ether, giving 11 g. of 1-benzyl-1H-tetrazole-5-carboxylic acid potassium salt.

Analysis for: C₉ H₇ KN₄ O₂ : Calculated: C, 44.61; H, 2.91; N, 23.13; Found: C, 44.26; H, 2.91; N, 23.27.

The potassium salt (7.27 g., 0.03 mol.) and 1.5 ml. of pryidine are stirred at 6° C. in 125 ml. of benzene, and 25 ml. of oxalyl chloride is rapidly added. After stirring 1/2 hour at 15° C. the mixture is stripped at 15° C., and scrubbed with two portions of 130 ml. of benzene at 15° C., giving a crude mixture of 1-benzyl-1H-tetrazole-5-carbonyl chloride. This preparation of the acid chloride is kept cold and used immediately for acylation.

1-Benzyl-1H-tetrazole-5-carbonyl chloride (0.06 mol.) is dissolved in methylene chloride, and added to a 5°-10° C. solution of 2-amino-6-methoxybenzamide (9.97 g., 0.06 mol.) and 5 ml. of pyridine in 270 ml. of methylene chloride. The reaction solution is stirred for 2 hours at room temperature, washed twice with water, twice with brine and dried over CaCl₂. Evaporation of the solvent gives 23 g. of a pink solid which crystallizes from acetonitrile giving 15.7 g. of 1 benzyl-N-[2-carbamoyl-3-methoxyphenyl]-1H-tetrazole-5-carboxamide, m.p. 190°-192° C.

Analysis for: C₁₇ H₁₆ N₆ O₃ : Calculated: C, 57.95; H, 4.58; N, 23.85; Found: C, 58.39; H, 4.63; N, 23.86.

The benzyl group is hydrogenolyzed from 13.43 g. of the above compound in 1100 ml. of acetic acid with 6.72 g. of 10% Pd/C. The product is crystallized from 1:1-methoxy-ethanol-water, giving 2.32 g. of the title compound, m.p. 249° C. (dec.).

Analysis for: C₁₀ H₁₀ N₆ O₃ : Calculated: C, 45.80; H, 3.84; N, 32.05; Found: C, 45.88; N, 4.14; N, 32.42.

The title compound exhibited the following dose-response relationship when administered to rats, orally, in the rat PCA test:

    ______________________________________                                         dose mg/kg       % inhibition                                                  ______________________________________                                         0.1              59                                                            1                65.8                                                          5                86.3                                                          10               100                                                           25               96.8                                                          50               100                                                           ______________________________________                                    

Thus, the anti-allergic compounds afforded by this specification result from the reaction of N-protected-1H-tetrazole-5-carbonyl chloride and the amine ANH₂ followed by deprotection of the product, where ANH₂ and the resulting final product are described below:

    ______________________________________                                         ANH.sub.2    Final Product                                                     ______________________________________                                         2-aminothiazole                                                                             N-[2-thiazolyl]-1H-tetrazole-5-                                                carboxamide                                                       2-aminopyridine                                                                             N-[2-Pyridyl]-1H-tetrazole-5-                                                  carboxamide                                                       2-aminonicotinonitrile                                                                      N-[3-cyano-2-pyridyl]-1H-tetrazole-                                            5-carboxamide                                                     2-aminopyrimidine                                                                           N-[2-pyrimidinyl]-1H-tetrazole-5-                                              carboxamide                                                       4-aminopyridine                                                                             N-[4-pyridyl]-1H-tetrazole-5-                                                  carboxamide                                                       3-aminopyridine                                                                             N-[3-pyridyl]-1H-tetrazole-5-                                                  carboxamide                                                       2-amino-6-picoline                                                                          N-[2-(6-methyl)pyridyl-1H-tetrazole-                                           5-carboxamide                                                     2-aminopyrazine                                                                             N-[2-pyrazinyl]-1H-tetrazole-5-                                                carboxamide                                                       Aniline      N-[2-pyrazinyl]-1H-tetrazole-5-                                                carboxamide                                                       2-aminobenzoic acid                                                                         N-[2-carboxyphenyl]-1H-tetrazole-                                              5-carboxamide                                                     2-aminobenzamide                                                                            N-[2-carbamoylphenyl]-1H-tetrazole-                                            5-carboxamide                                                     2-cyanoaniline                                                                              N-[2-cyanophenyl]-1H-tetrazole-5-                                              carboxamide                                                       2-methylaniline                                                                             N-[2-methylphenyl]-1H-tetrazole-                                               5-carboxamide                                                     2-methoxyaniline                                                                            N-[2-methoxyphenyl]-1H-tetrazole-                                              5-carboxamide                                                     3-methoxyaniline                                                                            N-[3-methoxyphenyl]-1H-tetrazole-                                              5-carboxamide                                                     3-trifluoromethyl-                                                                          N-[3-trifluoromethylphenyl]-1H-                                   aniline      tetrazole-5-carboxamide                                           3-fluoroaniline                                                                             N-[3-fluorophenyl]-1H-tetrazole-                                               5-carboxamide                                                     3-methylaniline                                                                             N-[3-methylphenyl]-1H-tetrazole-                                               5-carboxamide                                                     4-aminobenzamide                                                                            N-[4-carbamoylphenyl]-1H-tetrazole-                                            5-carboxamide                                                     4-methoxyaniline                                                                            N-[4-methoxyphenyl]-1H-tetrazole-                                              5-carboxamide                                                     4-methylaniline                                                                             N-[4-methylphenyl]-1H-tetrazole-                                               5-carboxamide                                                     2-amino-6-methoxy-                                                                          N-[2-carbamoyl-3-methoxyphenyl]-                                  benzamide    1H-tetrazole-5-carboxamide                                        2-amino-6-methoxy                                                                           N-[2-carboxy-3-methoxyphenyl]-1H-                                 benzoic acid tetrazole-5-carboxamide                                           2-cyano-3-methoxy-                                                                          N-[2-cyano-3-methoxyphenyl]-1H-                                   aniline      tetrazole-5-carboxamide                                           2-amino-6-chloro-                                                                           N-[2-carbamoyl-3-chlorophenyl]-1H-                                benzamide    tetrazole-5-carboxamide                                           2-amino-6-phenoxy-                                                                          N-[2-carbamoyl-3-phenoxyethoxy-                                   ethoxybenzamide                                                                             phenyl]-1H-tetrazole-5-carboxamide                                2-amino-5-methoxy                                                                           N-[2-carboxy-4-methoxyphenyl]-1H-                                 benzoic acid tetrazole-5-carboxamide                                           2-amino-5-chloro-                                                                           N-[2-carbamoyl-4-chlorophenyl]-                                   benzamide    1H-tetrazole-5-carboxamide                                        2-amino-4-methoxy-                                                                          N-2-carbamoyl-5-methoxyphenyl]-                                   benzamide    1H-tetrazole-5-carboxamide                                        5-chloro-2-sulf-                                                                            N-[5-chloro-2-sulfamoylphenyl]-                                   amoylaniline 1H-tetrazole-5-carboxamide                                        2,6-dichloroaniline                                                                         N-[2,6-dichlorophenyl]-1H-tetrazole-                                           5-carboxamide                                                     4-(4-ethoxycarbamido-                                                                       N-[4-(4-ethoxycarbamidophenoxy)-                                  phenoxy)aniline                                                                             phenyl]-1H-tetrazole-5-carboxamide                                2-amino-6-ethoxy-                                                                           N-[2-carbamoyl-3-ethoxyphenyl]-1H-                                benzamide    tetrazole-5-carboxamide                                           2-amino-6-propoxy-                                                                          N-[2-carbamoyl-3-propoxyphenyl]-                                  benzamide    1H-tetrazole-5-carboxamide                                        2-amino-6-isopropoxy-                                                                       N-[2-carbamoyl-3-isopropoxyphenyl]-                               benzamide    1H-tetrazole-5-carboxamide                                        2-amino-6-n-butoxy-                                                                         N-[2-carbamoyl-3-n-butoxyphenyl]-                                 benzamide    1H-tetrazole-5-carboxamide                                        2-naphthylamine                                                                             N-[2-naphthyl]-1H-tetrazole-5-                                                 carboxamide                                                       1-naphthylamine                                                                             N-[1-naphthyl]-1H-tetrazole-5-                                                 carboxamide                                                       3,4,5-trimethoxy-                                                                           N-[3,4,5-trimethoxyphenyl]-1H-                                    aniline      tetrazole-5-carboxamide                                           2-amino-6-methoxy-N-                                                                        N-[2-N-methylcarbamoyl-3-methoxy-                                 methylbenzamide                                                                             phenyl]-1H-tetrazole-5-carboxamide                                2-amino-6-(2-dimethyl-                                                                      N-[2-carbamoyl-3-(2-dimethylamino-                                aminoethoxy)-                                                                               ethoxy)phenyl]-1H-tetrazole-5-                                    benzamide    carboxamide                                                       4,5-dimethylanthra-                                                                         N-[2-carboxy-4,5-dimethylphenyl]-                                 nilic acid   1H-tetrazole-5-carboxamide                                        2-amino-4,5-dimethyl-                                                                       N-[2-carbamoyl-4,5-dimethylphenyl]-                               benzamide    1H-tetrazole-5-carboxamide                                        2-acetyl-3-methoxy-                                                                         N-2-acetyl-3-methoxyphenyl]-1H-                                   aniline      tetrazole-5-carboxamide                                           2-amino-6-(2-hydroxy-                                                                       N-[2-carbamoyl-3-(2-hydroxypropoxy)-                              propoxy)benzamide                                                                           phenyl]-1H-tetrazole-5-carboxamide                                2-amino-4,6-dimethyl-                                                                       N-[2-carbamoyl-3,5-dimethoxyphenyl]-                              oxybenzamide 1H-tetrazole-5-carboxamide                                        2-amino-6-(2-hydroxy-                                                                       N-[2-carbamoyl-3-(2-hydroxyethoxy)                                ethoxy)benzamide                                                                            phenyl]-1H-tetrazole-5-carboxamide                                2-amino-6-benzyloxy-                                                                        N-[2-carbamoyl-3-benzyloxyphenyl]-                                benzamide    1H-tetrazole-5-carboxamide                                        4-chloroaniline                                                                             N-[4-chlorophenyl)-1H-tetrazole-5-                                             carboxamide                                                       4-dimethylamino-                                                                            N-[4-dimethylaminophenyl]-1H                                      aniline      tetrazole-5-carboxamide                                           2-amino-6-dimethyl-                                                                         N-[2-carbamoyl-3-dimethylamino-                                   aminobenzamide                                                                              phenyl]-1H-tetrazole-5-carboxamide                                ______________________________________                                     

What is claimed is:
 1. A process for preventing the release of pharmocological mediators from an immediate hypersensitivity reaction between reaginic type antibodies and an antigen, thereby preventing the symptoms manifest in bronchial asthma, seasonal pollinosis, allergic rhinitis, urticaria, allergic conjunctivitis, food allergy and anaphylactoid reactions of a sensitized animal, which comprises prophylactically administering to said animal an effective amount of a compound of the formula: ##STR9## in which A is a member selected from the group consisting of α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower) alkoxy, 2-(lower alkoxy oxalyloxy)ethoxy, N-mono- and di-lower alkylamino(lower)alkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamoyl, N-lower alkylcarbamoyl, mono- and di-lower alkylamino, carboxy, lower alkylcarbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxy-oxalamido and lower alkoxyoxalamidophenoxy radicals;of a pharmaceutically acceptable salt thereof.
 2. The process of claim 1 which comprises administering to said sensitive animal a compound of the formula ##STR10## in which R¹ is --CN or CONH₂ ;R² is lower alkoxy, hydroxy(lower)alkoxy, lower alkylamino or di(lower)alkyl amino; R³ is hydrogen, lower alkyl, lower alkoxy, halo, poly-halo(lower)alkyl, lower alkyl carbonyl or carb(lower) alkoxy;or pharmaceutically acceptable salt thereof.
 3. The process of claim 1 in which said compound is of the formula: ##STR11## in which R² is lower alkylamino or di(lower)alkyl amino;R³ is hydrogen, lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb(lower) alkoxy;or pharmaceutically acceptable salt thereof.
 4. The process of claim 1 in which said compound is of the formula: ##STR12## in which R² is lower alkoxy or hydroxy(lower)alkoxy;R³ is hydrogen, lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb(lower)alkoxy;or pharmaceutically acceptable salt thereof.
 5. The process of claim 1 which comprises orally administering to said sensitized animal an effective amount of 1H-tetrazole-5-carboxanilide or a pharmaceutically acceptable salt thereof.
 6. The process of claim 1 which comprises orally administering to said sensitized animal an effective amount of N-[2-carbamyl-3-methoxyphenyl]-1H-tetrazole-5-carboxamide.
 7. A compound of the formula: ##STR13## in which A is α-naphthyl, β-naphthyl, 2,6-dichlorophenyl or a substituted phenyl moiety having from one to three substituents selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(lower alkoxyoxalyloxy)-ethoxy, N-mono- and di-(lower) alkylamino(lower) alkoxy, sulfamyl, polyhalo(lower) alkyl, carbamoyl, N-(lower)alkycarbamyl, mono- and di-(lower) alkylamino, carboxy, lower alkyl carbonyl, cyano, carb(lower)alkoxy, phenoxy(lower)alkoxy, lower alkoxyoxalamido and lower alkoxyoxalamidophenoxy;or a pharmaceutically acceptable salt thereof.
 8. A compound of the formula: ##STR14## in which R¹ is --CN or CONH₂ ;R² is lower alkoxy, hydroxy lower alkoxy, lower alkylamino or di(lower)alkyl amino; R³ is hydrogen, lower alkyl, lower alkoxy, halo, polyhalo(lower)alkyl, lower alkyl carbonyl or carb(lower)alkoxy;or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 8 in which is N-[2-carbamoyl-3-methoxyphenyl]-1H-tetrazole-5-carboxamide or a pharmaceutically acceptable salt thereof. 